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Recent Developments in Combination Chemotherapy for Colorectal and Breast Cancers with Topoisomerase Inhibitors.

ABSTRACT: DNA topoisomerases are important enzymes that stabilize DNA supercoiling and resolve entanglements. There are two main types of topoisomerases in all cells: type I, which causes single-stranded DNA breaks, and type II, which cuts double-stranded DNA. Topoisomerase activity is particularly increased in rapidly dividing cells, such as cancer cells. Topoisomerase inhibitors have been an effective chemotherapeutic option for the treatment of several cancers. In addition, combination cancer therapy with topoisomerase inhibitors may increase therapeutic efficacy and decrease resistance or side effects. Topoisomerase inhibitors are currently being used worldwide, including in the United States, and clinical trials on the combination of topoisomerase inhibitors with other drugs are currently underway. The primary objective of this review was to comprehensively analyze the current clinical landscape concerning the combined application of irinotecan, an extensively investigated type I topoisomerase inhibitor for colorectal cancer, and doxorubicin, an extensively researched type II topoisomerase inhibitor for breast cancer, while presenting a novel approach for cancer therapy.

SUBMITTER: Jang JY

PROVIDER: S-EPMC10178955 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Recent Developments in Combination Chemotherapy for Colorectal and Breast Cancers with Topoisomerase Inhibitors.

Jang Jung Yoon JY Kim Donghwan D Kim Nam Deuk ND

International journal of molecular sciences 20230508 9

DNA topoisomerases are important enzymes that stabilize DNA supercoiling and resolve entanglements. There are two main types of topoisomerases in all cells: type I, which causes single-stranded DNA breaks, and type II, which cuts double-stranded DNA. Topoisomerase activity is particularly increased in rapidly dividing cells, such as cancer cells. Topoisomerase inhibitors have been an effective chemotherapeutic option for the treatment of several cancers. In addition, combination cancer therapy w ...[more]

PMID: 37176164

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Project description:BackgroundBreast cancers are heterogeneous with variable clinical courses and treatment responses.ObjectiveWe sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents.Patients and methodsNewly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOnco®). Observed genomic changes were correlated with the Miller-Payne histological response to treatment.ResultsThirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2-/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029).ConclusionsSerial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy.Clinical trial registrationClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).

Dataset Information

Recent Developments in Combination Chemotherapy for Colorectal and Breast Cancers with Topoisomerase Inhibitors.

Publications

Recent Developments in Combination Chemotherapy for Colorectal and Breast Cancers with Topoisomerase Inhibitors.

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